Genome‐wide association analysis of age at onset in schizophrenia in a European‐American sample

We performed a genome‐wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene × gender interactions for AAO in schizophrenia (SCZ) using a European‐American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene × gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10 × 10^?7) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30 × 10^?6) and the third region was at 4p16.1 (rs17407555, P = 4.56 × 10^?6, near RAF1P1, and rs4697924, P = 1.23 × 10^?5 within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10 × 10^?6 and 2.33 × 10^?6, respectively) and strong gene × gender interactions in influencing AAO (P = 9.23 × 10^?7 and 1.15 × 10^?6, respectively) while the second best region showing gene × gender interaction was at 7q22.3 (rs179863, P = 2.33 × 10^?6). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ. © 2011 Wiley‐Liss, Inc.     

A Genome‐Wide Search for Type 2 Diabetes Susceptibility Genes in an Extended Arab Family

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome‐wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome‐wide significance (commonly P = 5 × 10^?8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12‐p13 (KCTD8: rs4407541, P = 9.70 × 10^?6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10^?6) and 14q13 (PRKD1: rs10144903, 3.92 × 10^?6), supported by analysis using a linear mixed model approximation in GenABEL (4p12‐p13 GABRG1/GABRA2: rs7662743, P_adj‐agesex = 2.06 × 10^?5; KCTD8: rs4407541, P_adj‐agesex = 1.42 × 10^?4; GABRB1: rs10517178/rs1372491, P_adj‐agesex = 0.027; 14q13 PRKD1: rs10144903, P_adj‐agesex = 6.95 × 10^?5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P_adj‐agesex = 0.030) and rs2055942 (P_adj‐agesex = 0.022) at COX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P_adj‐agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P_{adj‐agesex‐combined} = 3 × 10^?4) and at KCTD8 (rs4695718: P_{adj‐agesex‐combined} = 2 × 10^?4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P_adj‐agesex = 0.031; P_{adj‐agesex‐combined} = 2 × 10^?4). These genes may provide important functional leads in understanding disease pathogenesis in this population.     

Genome‐Wide Association Study Confirms SNPs in SNCA and the MAPT Region as Common Risk Factors for Parkinson Disease

Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome‐wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome‐wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p‐value = 6.7 × 10^?8; genome‐wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17–1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p‐value = 5.6 × 10^?8; genome‐wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62–0.79] T vs. C allele, PAR%= 8%) were genome‐wide significant. No other SNPs were genome‐wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.     

Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence

Event‐related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome‐wide association study (GWAS) of an ERO endophenotype—frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty‐two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family‐based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two‐stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10^?6). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10^?4), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM‐IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case–controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case–control and family‐based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. © 2010 Wiley‐Liss, Inc.     

A case–control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE)

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p‐value = 6.24 × 10^?8), rs74477937 (p‐value = 8.56 × 10^?8) and rs78707086 (p‐value = 8.55 × 10^?8) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta‐analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.     

Variants in 9p21 Predicts Severity of Coronary Artery Disease in a Chinese Han Population

Recent genome‐wide association studies identified the common genetic variants in 9p21 were associated with the coronary artery disease (CAD). However, whether this locus could predict the severity of CAD in Chinese Han population is unclear. 499 CAD patients who underwent coronary angiography (CAG) have been enrolled for this study. The single‐nucleotide polymorphisms rs2383207 and rs2383206 in 9p21 were genotyped in 499 CAG cases and 1519 controls in Chinese Han population. The gene dosage of 9p21 was stratified by the degree of vascular lesions and tested for association with the severity of CAD. Rs2383207 and rs2383206 demonstrated significant associations with 2‐vessel and 3‐vessel disease (P = 2.0×10^?3 and 1.9×10^?4, respectively). GG genotypes of rs2383206 occurred higher proportion of left main trunk (LM) disease (P = 6.0×10^?3). GG genotypes of rs2383207 occurred higher proportion of left anterior descending artery disease (LAD) and right CAD (RCA) (P = 2.7×10^?6 and 1.6×10^?4, respectively). The risk allele G of rs2383207 was associated with severity of CAD estimated by the Gensini score (P = 3.6×10^?5). Rs2383207 may strongly influence the development of CAD in Chinese Han population. The gene dosage in 9p21 could predict the severity of CAD.     

2p24.2 (rs7552) is a susceptibility locus for nonsyndromic cleft lip with or without cleft palate in the Brazilian population

The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here, we investigated 5 reported genome‐wide loci for NSCL±P in an ancestry‐structured case‐control study containing 1697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single‐markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL±P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31‐2.24, P = 9 × 10^?6) in the homozygous state. Several SNP‐SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3‐loci among rs7552, rs9891446 and rs73039426 (P = 6.1 × 10^?9 and p_{1000 permutation} = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL±P in the highly admixed Brazilian population.     

Genetic association and sequencing of the insulin‐like growth factor 1 gene in bipolar affective disorder

Insulin‐like growth factor 1 (IGF1) has been shown to have an important role in brain development and function. Studies of IGF1 administration in rodents have shown that it has an anxiolytic and antidepressant effect. A genome‐wide association study (GWAS) of the first University College London (UCL) cohort of 506 bipolar affective disorder subjects and 510 controls was carried out. The exons and flanking regions of IGF1 were resequenced, any new polymorphisms found were genotyped in an enlarged UCL sample of 937 cases and 941 controls. GWAS data gave good evidence of allelic and haplotypic association between multiple IGF1 SNP's and bipolar disorder (BD). New polymorphisms were found by resequencing IGF1 region. Data from GWAS and the new markers showed that twelve out of 43 SNPs showed association with BD with the four most significant SNPs having values of 3.7 × 10^?5, 8.4 × 10^?4, 2.6 × 10^?4, and 2.5 × 10^?4. A 5′ promoter microsatellite polymorphism previously correlated with plasma lipoprotein concentration was also associated with BD (P = 0.013). Haplotypic association confirmed association with BD with significance values similar to the single marker SNP values. The marker rs12426318 has also been found to be associated with BD in a second sample. A test of gene wide significance with permutation testing for all markers genotyped at IGF1 was also significant. These data implicate IGF1 as a candidate gene to cause genetic susceptibility to BD. © 2011 Wiley‐Liss, Inc.     

Genome‐wide association study of lncRNA polymorphisms with bone mineral density

Recent studies suggested that long noncoding RNAs (lncRNAs) were widely transcribed in the genome, but their potential roles in the genetic complexity of human disorders required further exploration. The purpose of the present study was to explore genetic polymorphisms of lncRNAs associated with bone mineral density (BMD) and its potential value. Based on the lncRNASNP database, 55,906 lncSNPs were selected to conduct a genome‐wide association study meta‐analysis among 11,140 individuals of seven independent studies for BMDs at femoral neck (FN), lumbar spine, and total hip (HIP). Promising results were replicated in Genetic Factors for Osteoporosis Consortium (GEFOS Sequencing, n = 32,965). We found two lncRNA loci that were significantly associated with BMD. MEF2C antisense RNA 1 (MEF2C‐AS1) located at 5q14.3 was significantly associated with FN‐BMD after Bonferroni correction, and the strongest association signal was detected at rs6894139 (P = 3.03 × 10^?9). LOC100506136 rs6465531 located at 7q21.3 showed significant association with HIP‐BMD (P = 7.43 × 10^?7). MEF2C‐AS1 rs6894139 was replicated in GEFOS Sequencing with P‐value of 1.43 × 10^?23. Our results illustrated the important role of polymorphisms in lncRNAs in determining variations of BMD and provided justification and evidence for subsequent functional studies.     

Evidence for Association between SH2B1 Gene Variants and Glycated Hemoglobin in Nondiabetic European American Young Adults: The Add Health Study

Glycated hemoglobin (HbA1c) is used to classify glycaemia and type 2 diabetes (T2D). Body mass index (BMI) is a predictor of HbA1c levels and T2D. We tested 43 established BMI and obesity loci for association with HbA1c in a nationally representative multiethnic sample of young adults from the National Longitudinal Study of Adolescent to Adult Health [Add Health: age 24–34 years; n = 5641 European Americans (EA); 1740 African Americans (AA); 1444 Hispanic Americans (HA)] without T2D, using two levels of covariate adjustment (Model 1: age, sex, smoking, and geographic region; Model 2: Model 1 covariates plus BMI). Bonferroni adjustment was made for 43 SNPs and we considered P < 0.0011 statistically significant. Means (SD) for HbA1c were 5.4% (0.3) in EA, 5.7% (0.4) in AA, and 5.5% (0.3) in HA. We observed significant evidence for association with HbA1c for two variants near SH2B1 in EA (rs4788102, P = 2.2 × 10^?4; rs7359397, P = 9.8 × 10^?4) for Model 1. Both results were attenuated after adjustment for BMI (rs4788102, P = 1.7 × 10^?3; rs7359397, P = 4.6 × 10^?3). No variant reached Bonferroni‐corrected significance in AA or HA. These results suggest that SH2B1 polymorphisms are associated with HbA1c, largely independent of BMI, in EA young adults.     

A genome-wide association study identifies FSHR rs2300441 associated with follicle-stimulating hormone levels

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play critical roles in female reproduction, while the underlying genetic basis is poorly understood. Genome-wide association studies (GWASs) of FSH and LH levels were conducted in 2590 Chinese females including 1882 polycystic ovary syndrome (PCOS) cases and 708 controls. GWAS for FSH level identified multiple variants at FSHR showing genome-wide significance with the top variant (rs2300441) located in the intron of FSHR. The A allele of rs2300441 led to a reduced level of FSH in the PCOS group (β = −.43, P = 6.70 × 10⁻¹⁴) as well as in the control group (β = −.35, P = 6.52 × 10⁻⁴). In the combined sample, this association was enhanced after adjusting for the PCOS status (before: β = −.38, P = 1.77 × 10⁻¹³; after: β = −.42, P = 3.33 × 10⁻¹⁶), suggesting the genetic effect is independent of the PCOS status. The rs2300441 explained sevenfold higher proportion of the FSH variance than the total variance explained by the two previously reported FSHR missense variants (rs2300441 R² = 1.40% vs rs6166 R² = 0.17%, rs6165 R² = 0.03%). GWAS for LH did not identify any genome-wide significant associations. In conclusion, we identified genome-wide significant association between variants in FSHR and circulating FSH first, with the top associated variant rs2300441 might be a primary contributor at the population level.     

Genetic Factors in Nonsmokers with Age‐Related Macular Degeneration Revealed Through Genome‐Wide Gene‐Environment Interaction Analysis

Relatively little is known about the interaction between genes and environment in the complex etiology of age‐related macular degeneration (AMD). This study aimed to identify novel factors associated with AMD by analyzing gene‐smoking interactions in a genome‐wide association study of 1207 AMD cases and 686 controls of Caucasian background with genotype data on 668,238 single nucleotide polymorphisms (SNPs) after quality control. Participants’ history of smoking at least 100 cigarettes lifetime was determined by a self‐administered questionnaire. SNP associations modeled the effect of the minor allele additively on AMD using logistic regression, with adjustment for age, sex, and ever/never smoking. Joint effects of SNPs and smoking were examined comparing a null model containing only age, sex, and smoking against an extended model including genotypic and interaction terms. Genome‐wide significant main effects were detected at three known AMD loci: CFH (P = 7.51×10^?30), ARMS2 (P = 1.94×10^?23), and RDBP/CFB/C2 (P = 4.37×10^?10), while joint effects analysis revealed three genomic regions with P < 10^?5. Analyses stratified by smoking found genetic associations largely restricted to nonsmokers, with one notable exception: the chromosome 18q22.1 intergenic SNP rs17073641 (between SERPINB8 and CDH7), more strongly associated in nonsmokers (OR = 0.57, P = 2.73 × 10^?5), with an inverse association among smokers (OR = 1.42, P = 0.00228), suggesting that smoking modifies the effect of some genetic polymorphisms on AMD risk.     

A Genetic Variant rs1020760at NFKB1 is Associated with Clinical Features of Psoriasis Vulgaris in a Han Chinese Population

Psoriasis vulgaris is a chronic inflammatory skin disease associated with complex genetic susceptibility. Recently, we identified a single‐nucleotide variant rs1020760 at NFKB1 significantly associated with psoriasis in a Han Chinese population in deep analysis of exome and targeted sequencing (P = 1.76 × 10^?8). To investigate the potential association between rs1020760 and phenotypes of psoriasis vulgaris, we performed a genotype–phenotype analysis. A total of 9946 cases and 9906 controls with detailed clinical and demographic information were involved in this study, while the genotype data of rs1020760 was available in the previous targeted sequencing study of psoriasis. Genotype‐based association testing revealed the additive model might provide the best fit for rs1020760 (P = 5.44 × 10^?8). Case‐only analysis showed that the distribution of allele G was significantly different between the cases with and without family history (P_allele = 4.07 × 10^?3,P_genotype = 5.75 × 10^?3). The differences in allele and genotype frequencies were observed between all the subphenotypes and controls except for the genotype frequency of the late onset subgroup, while no difference was found in case‐only analysis for the other two subphenotypes. Rs1020760 was preferentially associated with family history of psoriasis, implying that NFKB1 might not only play important roles in the development of psoriasis, but might also contribute to the special phenotypes of this disease.     

Evaluation of risk loci for schizophrenia derived from genome‐wide association studies in a German population

In the genome‐wide association study (GWAS) on schizophrenia [O'Donovan et al. (2008); Nat Genet 40:1053–1055] a UK‐sample of 479 cases with DSM‐IV schizophrenia was genotyped in comparison to control subjects with follow up of 12 putative loci in international replication sets of approximately 15,000 cases and controls. In these cohorts and a combined bipolar and schizophrenia UK‐sample, six single nucleotide polymorphisms (SNPs) supported association, with the strongest evidence for SNP‐marker rs1344706 at the zinc finger ZNF804A locus on chromosome 2q32.1 (P = 1.61 × 10^?7). We attempted replication of these findings in a German population of 2,154 individuals (632 with affective disorders, 937 with schizophrenia, and 585 controls), but found none of the GWAS risk alleles significantly associated with psychosis. Particularly rs1344706, initially surpassing the genome‐wide significance level in an extended phenotype of schizophrenia and affective disorder, produced consistently negative results. At the ZNF804A locus estimated Odds ratios reached 1.08 (0.93–1.26 95% CI) for the schizophrenia sample and 1.04 (0.90–1.20 95% CI) for the combined set of cases with schizophrenia and affective disorder. The main limitation of our study may be the reduced power of the sample size, but our data may be useful for future meta‐analysis of GWA data sets. Although GWAS have proven extraordinary successful in identifying susceptibility genes for complex genetic disorders, the hypothesis of common genetic variants in the complex group of the schizophrenic psychoses with small effect size but relatively high frequency is still put to further scrutiny. © 2011 Wiley‐Liss, Inc.     

Genetic Variants in MicroRNAs and Their Binding Sites Are Associated with the Risk of Parkinson Disease

MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA‐binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA‐related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR‐4519 (P value = 1.3×10^?5 and OR = 0.93) and rs11651671:A>G in miR‐548at‐5p (P value = 1.1×10^?6 and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR‐4519 and miR‐548at‐5p on PD. Among them, we experimentally showed that NSF is a direct target of miR‐4519. Furthermore, among 48,844 miRNA‐binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA‐binding site variants on miRNA‐mediated regulation of their host genes.     

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome‐wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m² per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10^?11), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10^–9); genetic distances at HLA were greater than at random markers (P = 1.6 × 10^–46). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10^–10). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.     

Genome‐wide analyses of psychological resilience in U.S. Army soldiers

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genome‐wide association studies (GWASs) of self‐assessed (by questionnaire) and outcome‐based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self‐assessed resilience (N = 11,492) was found to have significant common‐variant heritability (h² = 0.162, se = 0.050, p = 5.37 × 10^?4), and to be significantly negatively genetically correlated with neuroticism (r_g = ?0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome‐wide significant locus on an intergenic region on Chr 4 upstream from doublecortin‐like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [p = 5.65 × 10^?9] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch‐like family member 36 (KLHL36) was detected at gene‐wise genome‐wide significance [p = 1.89 × 10^?6]. A polygenic risk score derived from the self‐assessed resilience GWAS was not significantly associated with outcome‐based resilience. In very preliminary results, genome‐wide significant association with outcome‐based resilience was found for one locus (top SNP: rs12580015 [p = 2.37 × 10^?8]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress‐related psychopathology and point to new avenues for therapeutic intervention.     

Common obesity risk alleles in childhood attention‐deficit/hyperactivity disorder

Children with attention‐deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome‐wide association study (GWAS) for ADHD based on 495 patients and 1,300 population‐based controls and performed in silico analyses of the SNPs in an ADHD meta‐analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X‐type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10^?4; P_corr = 0.01). In the meta‐analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein‐coupled receptor, family C, group 5, member B; P = 7.2 × 10^?4; P_corr = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine‐6‐phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen‐activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta‐analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity. © 2013 Wiley Periodicals, Inc.